1. Field of the Invention
This invention relates generally to the fields of molecular biology and molecular medicine and, more specifically, to polypeptides involved in the regulation of apoptotic cell death.
2. Background Information
Apoptosis is the term used to describe a type of cellular death that occurs in many tissues as a normal physiological process. This form of cellular demise involves activation of a built-in genetic program for cell suicide by which cells essentially autodigest. Remnants of the dead cells are then cleared by neighboring phagocytic cells, without resulting in inflammation or scarring. Apoptosis thus stands in marked contrast to cell death caused, for example, by oxygen-deprivation in the settings of myocardial infarction or stroke, where cells lose their energy supplies, rupture and spill their contents into the extracellular milieu. This type of cell death, known as necrosis, often results in inflammation and undesirable consequences.
Apoptosis plays a role in many normal processes including tissue turnover, proper development and maintenance of the immune system, development of the nervous system, and elimination of virus-infected cells. It is a well-ordered process that is characterized by DNA fragmentation, chromatin condensation, membrane blebbing and cell shrinkage. Cells undergoing apoptosis ultimately disassemble into membrane-enclosed vesicles (apoptotic bodies) that are engulfed by neighboring cells and phagocytes, thus preventing an inflammatory response.
In contrast to the role of apoptosis in normal cellular processes, aberrantly regulated apoptotic cell death can lead to a variety of disease states and pathological conditions. As an example, dysregulation of apoptosis in the nervous system can result in unintended neuronal cell death which contributes to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). Additionally, viral infection can cause apoptosis such as T-cell apoptosis induced by the human immunodeficiency virus (HIV). The failure of normal apoptosis also can lead to disease, as in the case of autoimmune diseases in which immune cells that normally would have been eliminated through apoptosis attack normal tissues. Suppression of apoptosis can also contribute to tumorigenesis.
Integrin-mediated cell attachment is one of the main regulators of apoptosis. Most types of normal cells are anchorage-dependent; in these cells, the loss of integrin-mediated cell attachment to the extracellular matrix results in a subtype of apoptosis known as “anoikis.” Integrins suppress apoptosis (anoikis) in attached cells by activating signaling pathways that promote survival and by inactivating pathways that promote apoptosis. A number of these pathways, which vary in importance in different cell types, have been partially characterized. One integrin-regulated pathway initiates with activation of focal adhesion kinase (FAK) by extracellular matrix-bound integrins and results in the activation of PI3K and Akt/protein kinase B, providing a major source of survival signaling in many cell types. This pathway may function through inactivation of the pro-apoptotic proteins Bad and caspase-9. Direct binding and activation of a caspase-8 by unliganded integrins also can contribute to anoikis, an effect which is reversed by integrin binding to the extracellular matrix.
Bcl-2 is one anti-apoptotic protein that protects cells against anoikis. The α5β1 and αvβ3 integrins are particularly efficient in up-regulating Bcl-2 expression, whereas other integrins such as the αvβ1 integrin are ineffective. Akt activation through a FAK/Shc-Ras-PI3K pathway also can play a role in the Bcl-2-dependent survival pathway. Unfortunately, the molecules that participate in integrin regulation of Bcl-2 expression, which can be important diagnostic indicators as well as targets for therapeutic intervention, remain to be identified.
Thus, there exists a need to identify polypeptides that regulate anoikis, such as polypeptides that play a role in integrin regulation of Bcl-2 expression, as well as molecules that bind these polypeptides or modulate their interactions. The present invention satisfies this need and provides related advantages as well.